Production of 1-(nitrophenyl)-2 acylamidopropane-1, 3-diols



Patented Aug. 24, 1954 PRODUCTION OF 1- (NITROPHENYL) -2ACYLAMIDOPROPANE-1,3-DIOLS Loren M. Long, Grosse Pointe Woods, Mich.,assigner to Parke, Davis & Company, Detroit, Mich., a corporation ofMichigan No Drawing. Application January 26, 1953, Serial No. 333,379

1 This invention relates to a process for producing 1 p -'nitrophenyl-2- acylamidopropane-1,3-

diols. More particularly, the invention relates to an improved processfor producing threo-l-pnitrophenyl-2-acylamidopropane-1,3-diols fromp-nitro-a-acylamido-B-hydroxypropiophenones.

1-p-nitrophenyl-2-acylamidopropane-1,3- diols having the threodiastereoisomeric form are important therapeutic products orintermediates for the production of therapeutic products.

amido-p-hydroxypropiophenones with an oxi-- dizable aluminum alkoxide inan anhydrous organic solvent is perhaps the most practical andimportant. can Chemical Society, volume '71, pages 2473- [Long et al.,Journal of the Ameri-' 2475 (1949); ibid., volume '73, pages 481-482,

(1951)]. Although this process produces a mixture of diastereoisomerswhich is primarily composed of the desired threo diastereoisomer, theyield of this component is, for some unexplainable reason, never greaterthan 50% of the theoretical and is usually in the range of 40 to 45% ofthe theoretical. Moreover, even though only small amounts of the erythrodiastereoisomer are produced in the process some processing is usuallyrequired to purify the reduction product and this, of course, isundesirable.

It is an object of the invention to provide a method for obtaining highyields of the threo-ip-nitrophenyl-2-acylamidopropane-1,3-dio1s by thereduction of p-nitro-a-acylamido-[i-hydroxypropiophenones with anoxidizable aluminum alkoxide in an anhydrous organic solvent.

10 Claims. (Cl. 260562) Another object of the invention is to provide amethod for carrying out the reduction ofp-nitroa-acylamido-;3-hydroxypropiophenones with an oxidizable aluminumalkoxide to obtain threo-1- p-nitroph enyl 2 .acylamidopropane 1,3 diolswhich contain little or none of the erythro diastereoisomer. I

These and other objects which will appear hereinafter are realized bycarrying out the reduction ofp-nitro-a-acylamido-fl-hydroxypropiophenones with an oxidizable aluminumalkoxide in an anhydrous organic solvent in the presence of an aluminumhalide, preferably aluminum chloride or aluminum bromide. Carrying outthe reaction in the presence of an aluminum halide results in a 10 to40% increase in yield over the best yield obtainable without the use ofan aluminum halide catalyst. So far as it has been possible todetermine, none or practically none of the erythro-l-p-nitrophenyl-2-acylamidopropane-1,3-diol is produced when an aluminum halide catalystis employed in the process.

In carrying out the process of the present invention, about 0.05 to 0.2mole of the aluminum halide is employed for each mole of thep-nitroa-acylamido-p-hydroxypropiophenone to be reduced. In general, thepreferred quantity of the aluminum halide is about 0.1 to 0.15 mole foreach mole of the ketonic compound to be reduced. The yield of thethreo-l-p-nitrophenyl- 2-acylamidopropane-1,3-diol obtained when usingthis preferred quantity of aluminum halide is generally to greater thanthe best yield obtainable without the use of a catalyst. When 0.05 moleof aluminum halide per mole of ketonic compound is employed the yieldis. about 10% greater than that obatined without the use of a catalyst.More than 0.2 mole of the aluminum halide per mole of the ketoniccompound can be employed, if desired, but this is uneconomical becausesuch larger amounts of catalyst do not appear to increase the yield. Thefollowing table illustrates the effect of the catalyst and the relativequantity thereof on the yield obtained in the reduction ofp-nitro-a-acylamido-B-hydroxypropiophenones with oxidizable aluminumalkoxides.

Amount of (rill-pnitro-a-acetamido- Amount of Alumi- Amount of Alumi-B-hydroxy-propionum Isopropycc of num Chloride g g g gfigengne to berelate "Used propanol (Catalyst) panedyg m 01 (Solvent) Grams MolesGrams Moles Grams Moles Grams Percent MZ. 15. 12 0. 05 18. 36 0. 09 2100 6. 2 40. 15. 12 O. 06 18. 36 0. 09 230 O 0 6. 8 44. 5 50. 4 0. 2 61. 20. 3 500 0 0 25 49. 2 50. 4 O. 2 40. 8 0. 2 1 500 0 0 13. 5 26. 8 50. 40. 2 45 0. 22 500 1. 34 0. 01 27. 5 54. 5 50. 4 0. 2 45 0. 22 500 2. 670. 02 32. 6 64 51 51 300 2. 67 0. 02 34 66 50. 4 0. 2 45 500 3 35 68. 750. 4 0. 2 61. 2 0. 3 500 4. 0 0. 03 36 70. 8 50. 4 0. 2 40. 8 0. 2 5005. 3 0. O4 35. 5 69. 8 50. 4 0. 2 61. 2 0. 3 500 13. 4 0. 1 35. 4 69. 750. 4 0. 2 45 0. 22 500 5 6. 34 7 0. O2 31. 3 61. 6

1 Plus 250 cc. of toluene. 1 AlBra rather than A101 The reaction can becarried out under a variety Example 1 of conditions. The organic solventused as the reaction medium is usually a lower aliphatic alcohol and,preferably, the one corresponding to the alkoxide. The use of alkoxidesof secondary alcohols such as isopropanol and secondary butyl alcohol ispreferred since these alkoxides are more readily oxidized and hencemilder reaction conditions can be employed. In general, the reaction canbe efifected over a widetemperature range, but for most purposes atemperature between about and'l25 C. is preferred. Similarly, the amountof the oxidizable aluminum alkoxide in relationship to thequantity ofthe ketonic compound to be reduced can be varied within rather largelimits. In most cases, it is seldom necessary to employ more than aboutthree equivalents of the alkoxide but, if desired, as little as oneequivalent to as much as twenty or thirty equivalents can be used. Whenusing an alkoxide derived from a secondary aliphatic alcohol in asolvent of the alcohol corresponding to the alkoxide, the preferredmethod of bringing about the reaction'is to reflux the reaction mixturecontaining one or slightly more equivalents of the aluminum alkoxide andto distill off the oxidized alcohol (a lower aliphatic ketone) as it isformed in the reaction mixture.

The process of the invention is generally-applicable to thep-nitro-aacylamido-c-hydroxypropiophenones and is not dependent upon thenature of the carboxylic acid acyl grouppresent in the ketonic startingmaterial. For example p nitro c: acylamido c hydroxypropiophenones inwhich the acyl group is derived from lower aliphatic carboxylic acids,halogenated lower aliphatic carboxylic acids, alkoxy lower aliphaticcarboxylic acids, benzoic acid, benzoic acids containing alkyl, alkoxy,halogen or nitro substituents and the like can be used as startingmaterials in the process. Similarly, the optical configuration of theketonic starting materials is not afiected by the reduction and,consequently, one can produce the optically active acylamido diols byutilizing an optically active ketonic compound as the starting material.It is, therefore, to be understood that, in the absence of a designationto the contrary, the chemical names used in thi specification and claimsare to be interpreted in their generic sense, that is, as including theindividual optical isomers as well as the racemic, modification of theketonic starting materials and final products.

The invention is illustrated by the following examples.

50.4 g. of ((12) -p-nitro-a-acetamido-;8-hydroxy propiophenone is addedportionwise with stirring over a period of fifty minutes to a refluxingsolution consisting of 61.2 g. of aluminum isopropylate, 4 g. ofanhydrous aluminum chloride and 500 cc. of anhydrous isopropanol. Theyellow solution gradually becomes a dark red-brown color as the additionprogresses. After the addition is completed the mixture is heated atreflux for one hour during which time the acetone is removed bydistillation along with a. small amount of the isopropanol. The mixtureis cooled slightly, cc. of water added and the resulting mixture stirredand refluxed for ten minutes. The hot mixture is filtered and theinsoluble aluminum hydroxide extracted with two 250 cc. portions of hot80% isopropanol and then with one cc. portion of hot isopropanol. Theextracts are combined with the reaction mixture filtrate and the waterand isopropanol removed by distillation in vacuo. The dryresidue isground up and refluxed for a few minutes with 200 cc. of ethyl acetate.The hot ethyl acetate mixture is cooled and the crystalline DL threo 1 pnitrophenyl 2 -acetamidopropane-1,3-diol collected and dried; yield 36g., 70.8% M. P. 164-6 C.

When the above procedure is followed omitting the 4 g. of anhydrousaluminum chloride the yield is only 49.2%.

Example 2 64.2 g. of (d2)-p-nitro-a-dichloroacetamidoflhydroxypropiophenone is added gradually with stirring to a refluxingsolution composed of 61.2 g. of aluminum isopropylate dissolved in 1000cc. of anhydrous isopropanol. The mixture is refiuxed for a total ofthree hours during which time a small amount of the reaction mixture isremoved by distillation. 290 cc. of water is added to the hot solution,the mixture refluxed for fifteen minutes and then filtered while hot.The residue is extracted with one liter of hot 80% isopropanol and thefiltrate and extract combined. The solvents are removed from thesolution by distillation in vacuo and the residue stirred with 300 cc.of hot ethyl acetate. The ethyl acetate mixture is cooled and thecrystalline DL-threo- 1 p nitrophenyl 2dichloroacetamidopropane-1,3-diol collected; M. P. 152 0.; yield, 24 g.,37%.

If 4 g. of anhydrous aluminum chloride is added to the aluminumisopropylate solution in the above procedure one obtains 42.2 g. ofDL-threo- 1 p nitrophenyl 2 dichloroacetamidopropane-LB-diol rather than24 g. The percentage yield is increased from 37% to 65%.

Example 3 50.4 g. of (dl) -p-nitro-a-acetamido-;8-hydroxypropiophenoneis added slowly to a refluxing mixture composed of 45 g. of aluminumisopropylate, 6.34 g. of anhydrous aluminum bromide and 500 cc. ofanhydrous isopropanol.

by distillation in vacuo. The residual yellow solid is warmed with about200 cc. of ethyl acetate; the mixture coled and thecrystallineDL-threo-lp nitrophenyl 2 acetamidopropane 1,3- diol collected; M. P. 164-4; C. yield, 31.3 g., 61.5%.

When the above procedure is carried out in the absence of aluminumbromide, the yield of the DL threo 1 p nitrophenyl 2acetamidopropane-1,3 diol is only 49.2%.

What I claim is:

1. In a process for the production of threo-1-p-nitrophenyl-2-acylamidopropane-1,3 diols by the reduction ofp-nitro-a-acylamido-fl-hydroxypropiophenones with an oxidizablealuminumv alkoxide in an anhydrous organic solvent, the improvementwhich comprises carrying out the reduction in the presence of analuminum halide.

2. Process according to claim 1 wherein 0.05

r to 0.2 mole of aluminum halide is employed for Th reaction mixture isheated and stirred for two hours during 4. In a process for theproduction of threo-lthe reduction of(dl)-p-nitro-a-acetamido-phydroxypropiophenone with an oxidizablealuminum alkoxide in an anhydrous organic solvent, the improvement whichcomprises carrying out the reduction in the presence of 0.05 to 0.2 moleof aluminum chloride for each mole'of the (61)-p-nitro-u-acetamido-p-hydroxypropiophenone to be reduced.

6. In a process for the production of DL-thre'o-1p-nitrophenyl-2-acetamidopropane-1,3-diol by the reduction of (d1)-p-nitro-a-acetamido-fihydroxypropiophenone with an oxidizable aluminumalkcxide in an anhydrous organic solvent, the improvement whichcomprises carrying out the reduction in the presence of 0.05 to 0.2 moleof aluminum bromide for each mole of the (d1)-p-nitro-a-acetamido-fi-hydroxypropiophenone to be reduced.

7. In a process for the production of DL-threol-p-nitrophenyl 2dichloroacetamidopropane- 1,3-diol by the reduction of (d1)-p-nitro-a-di chloroacetamido-fi-hydroxypropiophenone with an oxidizablealuminum alkoxide in an anhydrous organic solvent, the improvement whichcomprises carrying out the reduction in the presence of 0.05 to 0.2 moleof aluminum chloride for each mole of the(d1)-p-nitro-a-dichloroacetamido-phydroxypropiophenone to be reduced.

8. In a process for the production of DL-threo-1-p-nitrophenyl-2-acetamidopropane-1,3-diol by the reduction of (d1)-p-nitro-a-acetamido- 3- hydroxypropiophenone with aluminum isopropylatein anhydrous isopropanol, the improvement which comprises carrying outthe reduction in the presence of 0.05 to 0.2 mole of aluminum chloridefor each mole of the (dl)-p-nitro-aacetamido-p-hydroxypropiophenone tobe reduced.

9. In a process for the production of DL-threo-1-p-nitrophenyl-2-acetamidopropane-1.3-diol by the reduction of(dl)-p-nitro-u-acetamid0-B- hydroxypropiophenone with aluminumisopropylate in anhydrous isopropanol, the improvement which comprisescarrying out the reduction in the presence of 0.05 to 0.2 mole ofaluminum bromide for each mole of the (d1)-p-nitro-aacetamido-p-hydroxypropiophenone to be reduced.

10. In a process for the production of DL- threo1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol by the reduction of(dD-p-nitroa-dichloroacetamido c hydroxypropiophenone with aluminumisopropylate in anhydrous isopropanol, the improvement which comprisescarrying out the reduction in the presence of 0.05 to 0.2 mole ofaluminum chloride for each mole of the(dl)-p-nitro-a-dichloroacetamido-18-hydroxypropiophenone to be reduced.

No references cited.

1. IN A PROCESS FOR THE PRODUCTION OFTHREO-1P-NITROPHENYL-2-ACYLAMIDOPROPANE-2,3 - DIOLS BY THE REDUCTION OFP-NITRO-A-ACYLAMIDO-B-HYDROXYPROPIOPHENONES WITH AN OXIDIZABLE ALUMINUMALKOXIDE IN AN ANHYDROUS ORGANIC SOLVENT, THE IMPROVEMENT WHICHCOMPRISES CARRYING OUT THE REDUCTION IN THE PRESENCE OF AN ALUMINUMHALIDE.